Sudden cardiac arrest (SCA) is a major public health concern, accounting for over 400,000 deaths in the US each year. While environmental factors clearly contribute to the determinants of SCA, familial aggregation studies and advances in the molecular genetics of inherited arrhythmias suggest that genetic factors confer susceptibility to SCA in the general population. Identifying these genetic factors will not only provide insight into the mechanisms of SCA, it will also have significant public health implications for risk stratification and prevention of SCA. We propose to systematically investigate the association of SCA and intermediate phenotypes with variations in biologically important molecular pathways involved in arrhythmogenesis using complete sequence information and haplotype analyses. Specifically, we will study the association of SCA risk with variation in candidate genes (Aim 1) that are proximal determinants of electrogenesis and propagation (e.g. cardiac ion channel genes and connexins) and genes in pathways that influence these proximal determinants (e.g. neurohumoral modulators). We will explore these associations in the context of the genetic and environmental milieu, investigating interactions with medications (Aim 2a), exercise (Aim 2b), and other genetic factors (Aim 2c). We will also examine main effects of genetic variation on intermediate quantitative phenotypes, such as ECG QT interval, heart rate, and heart rate variability (Aim 3). This application represents a multi-center collaborative effort to efficiently combine advances in genomics with material from four on-going studies that enable rigorous identification of the SCA phenotype or relevant intermediate phenotypes. Specifically, we will use material from a large population-based repository of SCA cases (Cardiac Arrest Blood Repository), two case-control studies (Cardiac Arrest Blood Study and Group Health Cooperative study), and a cohort study (Cardiovascular Health Study):